rs397509425
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_021971.4(GMPPB):c.553C>T(p.Arg185Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R185H) has been classified as Uncertain significance.
Frequency
Consequence
NM_021971.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GMPPB | NM_021971.4 | c.553C>T | p.Arg185Cys | missense_variant | 5/9 | ENST00000308388.7 | |
GMPPB | NM_013334.4 | c.553C>T | p.Arg185Cys | missense_variant | 5/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GMPPB | ENST00000308388.7 | c.553C>T | p.Arg185Cys | missense_variant | 5/9 | 1 | NM_021971.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152216Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000359 AC: 9AN: 250734Hom.: 0 AF XY: 0.0000369 AC XY: 5AN XY: 135520
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461536Hom.: 0 Cov.: 44 AF XY: 0.0000110 AC XY: 8AN XY: 727060
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152334Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74490
ClinVar
Submissions by phenotype
Muscular dystrophy-dystroglycanopathy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | May 29, 2019 | This variant has been previously reported as a homozygous change in 6 patients with hypotonia, muscle weakness, cataracts, and elevated serum creatine kinase (PMID: 23768512, 29054425). Functional studies have shown reduced alpha-dystroglycan glycosylation in muscle and fibroblasts of individuals with this variant (PMID: 23768512). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0036% (9/250,734) and thus is presumed to be rare. The c.553C>T (p.Arg185Cys) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.553C>T (p.Arg185Cys) variant is classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | May 23, 2017 | - - |
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14;C3809221:Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B14;C4518000:Autosomal recessive limb-girdle muscular dystrophy type 2T Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | UCLA Clinical Genomics Center, UCLA | Jan 28, 2014 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 16, 2022 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on GMPPB function (PMID: 23768512). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 60543). This missense change has been observed in individuals with clinical features of GMPPB-related conditions (PMID: 23768512, 25326637, 30684953, 32403337, 32404165). This variant is present in population databases (rs397509425, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 185 of the GMPPB protein (p.Arg185Cys). - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 07, 2017 | - - |
Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B14 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 11, 2013 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 27, 2022 | - - |
Autosomal recessive limb-girdle muscular dystrophy type 2T Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 11, 2013 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at